The neglected continuously emerging Marburg virus disease in Africa: A global public health threat

Abstract Background and Aim Severe viral hemorrhagic fever (VHF) is caused by Marburg virus which is a member of the Filoviridae (filovirus) family. Many Marburg virus disease (MVD) outbreaks are reported in five decades. A major notable outbreak with substantial reported cases of infections and deaths was in 2022 in Uganda. The World Health Organisation (WHO) reported MVD outbreak in Ghana in July 2022 following the detection of two probable VHF patients there. Further, the virus was reported from two other African countries, the Equatorial Guinea (February 2023) and Tanzania (March 2023). There have been 35 deaths out of 40 reported cases in Equatorial Guinea, and six of the nine confirmed cases in Tanzania so far. Methods Data particularly on the several MVD outbreaks as reported from the African countries were searched on various databases including the Pubmed, Scopus, and Web‐of‐science. Also, the primary data and reports from health agencies like the WHO and the Centers for Disease Control and Prevention CDC) were evaluated and the efficacy reviewed. Results Chiroptera in general and bat species like Rousettus aegyptiacus and Hipposideros caffer in particular are natural reservoirs of the Marburg virus. MVD‐infected nonhuman primate African fruit‐bat and the MVD‐infected humans pose significant risk in human infections. Cross‐border viral transmission and its potential further international ramification concerns raise the risk of its rapid spread and a potential outbreak. Occurrence of MVD is becoming more frequent in Africa with higher case fatality rates. Effective prophylactic and therapeutic interventions to counter this deadly virus are suggested. Conclusion In the face of the lack of effective therapeutics and preventives against MVD, supportive care is the only available option which contributes to the growing concern and disease severity. In view of the preventive approaches involving effective surveillance and monitoring system following the “One Health” model is extremely beneficial to ensure a healthy world for all, this article aims at emphasizing several MVD outbreaks, epidemiology, zoonosis of the virus, current treatment strategies, risk assessments, and the mitigation strategies against MVD.

there were from Bukoba district of Kagera region.While the origin of the recent Ghana and Equatorial Guinea MVD outbreak is unidentified, the Tanzania outbreak was linked to Goziba Island in Lake Victoria, Tanzania.Nonetheless, these current MVD outbreaks were the first identified and reported from Ghana, Equatorial Guinea and the United Republic of Tanzania.
Known as Marburg hemorrhagic fever (MHF) earlier, MVD is certainly an illness of concern in humans and nonhuman primates that could turn fatal, 1,5 characterized by hemorrhagic fever with high morbidity and fatality rates (66.7%-75%CFR).Represented by one Ravn virus sp., Marburg virus, like Ebola, belongs to family Filoviridae.
The virus is pleomorphic which could be filamentous (892 nm length and 91 nm diameter), circular, or in the configuration of the digit "6". 6pically they are shepherd's crook shaped, "U" shaped, "6" shaped (like filoviruses) filaments, and could also be coiled, toroidal, or branched.These virions typically are of 80 nm width and may slightly vary in length.They typically have a median length of 795-828 nm as opposed to Ebola virion which has 974-1086 nm median length, although tissue culture revealed the viral particles as 14,000 nm large. 7Like all mononega viruses, MVD virions are noninfectious, linear, nonsegmented, single-stranded RNA genomes with negative polarity, inverse-complementary 3′ and 5′ termini, no 5′ cap, no polyadenylation, and no covalent protein attachment.Glycoprotein, viral protein 4, viral protein 24, nucleoprotein, viral protein 35 (polymerase cofactor), viral protein 30 (transcription activator) and L (RNA-dependent RNA polymerase) are the seven proteins encoded by this lipid-enveloped Marburg virus.MVD virus genome is about 19 kbp long and contains seven genes in 3′-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5′-UTR sequence. 8The cells lacking the Niemann-Pick C1 (NPC1) survived and seemed immune to Ebola virus at least in lab settings, proving that the virus needed NPC1 for cell entry. 9Thus, NPC1 cholesterol transporter protein is assumed to be needed in the infection of Marburg and Ebola viruses.
Ugandan studies identified the bat species R. aegyptiacus as the MVD virus reservoir. 6,10Direct or indirect contacts with fluids transmitted the disease to humans and others. 11,12Due to the associated significant risk to public health, MVD virus is categorised as a Tier-1 select agent by the Centers for Disease Control and Prevention (CDC) and a high priority category A pathogen by the WHO. 13 The WHO classifies it as a pathogen in risk group 4 requiring biosafety level 4-equivalent containment in view of its lethality. 14We emphasise on several MVD outbreaks, epidemiology, zoonosis of the virus, current treatment strategies, risk assessments and the mitigation strategies to counter the spread of this fatal disease.

| MATERIALS
This narrative review work started with sourcing of data from published literature available on public domain.Reports on the several MVD outbreaks in African countries were searched from various databases including the Pubmed, Scopus, and Web-ofscience.The primary data and reports from health agencies like the WHO and CDC were also evaluated and reviewed.A total of 53 articles/data sets were shortlisted out of a total 112 collated after searching, and the references were validated and manually listed.To avoid defocusing from the write-up, irrelevant or less meaningful articles were excluded.The transmission was allegedly triggered with the import of infected African green monkey (Cercopithecus aethiops) to develop polio vaccine. 13Supposedly the first ever discovery of filovirus, 17 it caused an uncommon but severe hemorrhagic fever (MVD) in both humans and nonhuman primates.9 Ghana reported four confirmed cases and three associated deaths in 2022. 3Table 1 depicts the timeline of the occurrence of MVD.

| MVD Outbreaks to date
Ugandan grivets (Chlorocebus aethiops), their tissues or organs transmitted the virus to laboratory personnel in Germany and Yugoslavia. 13,21Contact with the monkey was the primary cause of the usually reported nosocomial transmission. 11Numerous deaths with suspected hemorrhagic fever in the Equatorial Guinea were reported by their Ministry of Health and Social Welfare.The real-time polymerase chain reaction (RT-PCR) of the samples on February 12, 2023 confirmed one MVD positive case. 22A 34-year-old male traveler to Central Africa was the first reported suspected case from Valencia, Spain. 23More than 200 people in Equatorial Guinea were MVD quarantined, as per the Spanish health agency.

| Epidemiology of MVD
Marburg virus is a zoonotic virus of the Ebola virus family that could be contracted from the animal reservoir fruit-bat (R. aegyptiacus), its contaminated oral secretions that contaminate the partially eaten fruit and excreta. 24,25It carries the virus without falling sick being the reservoir, however severe-to-fatal viral hemorrhagic fever could occur when the virus infects a human.Bat species like Hipposideros caffer and other Chiropterans also are likely source of infection. 26The virus spreads through direct contact with the wound, scrape, or mucous membranes of the eyes, nose, or mouth.It could also spread through blood or body fluids like urine, sweat, faeces, vomit, breast milk, amniotic fluid, and sperm of an alive or dead MVD patient. 1 Also, it could be contracted from contaminated inanimate objects especially in hospital settings, like the medical supply, needle, bedding, or clothing in the MVD patient's ward.Another transmission object could be the sperm from oral, vaginal, or anal sexual activity of a MVD survivor, as the virus still persists in bodily fluids (including sperm) even though a convalescing patient may not exhibit acute MVD illness symptoms.MARV transmission by interacting with or touching the vaginal secretions of a MVD patient is not evidenced.
With varying (2-21 days) incubation period, 1 MVD fatality ranges from 22.6% to 100% (Table 2).MVD manifests as high fever, severe headache, and severe malaise.Abdominal pain, severe watery diarrhoea, nausea, and vomiting may follow from the third day.This shall follow severe hemorrhagic manifestations from fifth to seventh day with the patient bleeding from multiple areas in fatal cases.Due to heavy loss blood loss and shock, death mostly occurs by the eight or nineth day.Clinical diagnosis of MVD is confusing with other tropical febrile illnesses (malaria, typhoid, shigellosis, meningitis, and other VHFs) during early stage due to similar clinical symptoms. 28veral MVD diagnostic techniques including reverse transcriptionpolymerase chain reaction (RT-PCR) for viral RNA identification and enzyme-linked immunosorbent assay (ELISA) for antibody detection are available.Further, MARV infection is confirmed through serum neutralisation test, virus isolation through cell culture, and electron microscopy. 29Being extremely biohazardous, sample collection is risky, and thus laboratory testing may be carried out under maximum biological containment setting.All such specimen may be triplepackaged while transporting.Nevertheless, it necessitates expert laboratory set-up with skilled manpower that is often lacking in a resource-limited region where MVD outbreaks are frequent. 30,31

| Marv zoonosis
There is a constant threat of the emergence of infections given the crossover potential of microbes from animals and ecohabitats to humans.3][34] The emerging and reemerging of such diseases especially in the African continent is reportedly on the rise. 35A major contributing factor to the spread of zoonotic infections is the unhindered crossborder mobility of animals.This is glaringly evident from the emerging dengue and chikungunya cases in the European region that were nonexistent. 36The science, social, and natural science research could be integrated for better preparedness and effective management of zoonotic diseases. 37e fruit-bat (R. aegyptiacus) is considered the primary reservoir, 1,24,25  Paramyxoviridae and Rhabdoviridae among several other viruses.
Colonizing microbes may be analyzed using next-generation sequencing (NGS) and metagenome-based surveillance to identify prevailing microbial species to predict future outbreaks and implement effective preventive measures. 38,39

| MITIGATION STRATEGIES
The virus is assumed to zoonotically (animal-human) spread through fruitbat, and can spread between humans through contacts with the body fluid, chapped skin, and unprotected intercourse with the infected.The illness has Ebola-like symptoms of fever and hemorrhage.Although related, Marburg virus is not the same as Ebola virus.The unceasing hysteria around Ebola virus disease contributed significantly to absurd actions by the community during outbreaks. 6The MVD seems more severe and the survivor and the family are often stigmatized.MVD epidemic poses significant global public health emergency and mandates global cooperation to tackle it effectively.As the affected country may be resource-poor to counter the illness, the WHO, the World Bank, the International Monetary Fund (IMF), and others could extend technical and financial aids to garner necessary resources. 40Transmission of MVD via sexual route is noticed like the recently reemerged mpox. 21Thus, initiating community involvement is important as a measure in the course of preventive strategies.

| CURRENT TREATMENT STRATEGIES
No specific approved antiviral treatment for MVD is yet available, and hydration, pain management, and secondary infection treatment remain the mainstay as supportive care. 41 animal model. 42

| VACCINES DEVELOPMENT
Vaccines seem to be crucial in current situation when several outbreaks are encountered. 43Availability of licensed vaccines/medications and timely treatment of MVD symptoms like dehydration significantly increases the likelihood of survival, the WHO states. 44Supportive hospital care to manage patient's fluids, balance the electrolyte, maintain the blood pressure and oxygen levels, restore the lost blood, addressing the clotting components, and treating an exacerbating infection is important.In line with the Ebola response strategy, healthcare system is making all efforts to curb the spread of MVD virus, from raising public awareness, sensitizing, and supporting them to mobilizing the resources.
Nonhuman primates have been treated effectively that are yet to be tried on humans. 45 it induced neutralizing antibodies in 95% cases, results demonstrated that nearly half of the volunteers developed mild vaccination side-effects like pain at injection site, malaise, headache, and myalgia. 47

| THE STATUS OF THE NEGLECTED DISEASE
The WHO classifies MVD as a neglected tropical disease, owing to its neglected research, funding, and attention status as compared to other infectious diseases.Lack of commercial incentives for drug development and limited investments in MVD vaccine development have hindered the progress. 48In view of this, the global health agencies, governments, and nongovernmental organizations may prioritize MVD-specific research and development.Strengthening the surveillance and diagnostic capacities in particularly the endemic regions may aid in expeditious detection and response, and could also potentially prevent an outbreak from ramifying.

| RISKS ASSESSMENT
Making the general public aware about the risk factors and involving the community is an effective way to reduce viral transmission.
Considering the greater risk, miners and tourists visiting the fruit-bat inhabiting caves should follow adequate safety measures.They as also the treating healthcare workers need to be cautious and wear personal protective equipments (PPE), face protection (medical mask and goggles), and gloves as long as it is practicable.Healthcare and laboratory personnel could use nonsterile long-sleeved gown while dealing with suspected or confirmed MVD cases.Animal products may thoroughly be cooked before consumption to reduce the risk of the zoonotic (bat-to-human) transmission.Basic preventative measures in piggeries are warranted as pigs could potentially amplify an outbreak. 29The WHO recommends safe sex (semen must test negative) for convalescing male survivors of MVD to prevent possible risk of sexual transmission.with high infectivity and death rate which is a significant public health worry.Thus, tacking and managing MVD appears to be an international issue sooner-or-later that calls for global cooperation.
Research on anti-MARV vaccines and antivirals development may be prioritized and expedited.

| THE ONE-HEALTH APPROACH
The countries in the African continent have prioritized zoonotic illnesses as important public health concern to collaboratively tackle and close the gap through the cooperation of various departments that deal with humans, animals, and the environmental health through the "One Health" strategy.The Ghana Health Service Developing a workforce, monitoring systems for zoonoses, enhancing the national laboratory infrastructure, and prioritizing an action plan for zoonotic illnesses are some aspects that could be promoted so as to improve the capacity to quickly detect and respond to zoonotic infections in line with "One Health".

| GLOBAL PUBLIC HEALTH IMPLICATIONS
Despite its regional prevalence, the potential of MVD to internationally ramify is a pressing concern.Trade globalization, increased travel, and migration would facilitate global spread of the virus, potentially leading to outbreaks in nonendemic regions.To begin with, addressing the MVD issue requires international collaboration, research funding, and capacity-building especially in the endemic regions.The "global health security agenda," an international partnering aiming at preventing, detecting, and responding to threats of infectious diseases, could prioritize MVD for surveillance and preparedness.The MVD could additionally effectively be addressed through coordinated efforts of public health agencies, the policymakers, and the researchers through information and resource sharing. 51f the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Dehydration is managed and organ function is maintained by administering intravenous fluids and replacing electrolyte.Mortality rate remains high due to rapid progression of the disease and limited treatment alternatives.Further, the availability and accessibility of these life-saving interventions in the outbreak-prone regions is challenging.Therapeutics (drugs) and prophylactics (vaccines) are at advance research and development stages, offering hope to control future outbreak.For instance, targeted lipid-encapsulated siRNA inhibited MVD virus replication and reduced the mortality as demonstrated in Merck developed a potential recombinant vesicular stomatitis viral vaccine (rVSV-MARV) against MVD for Canada Public Health Agency to be discontinued later.Numerous MARV vaccines being researched seem promising.Recombinant VSV-based MARV glycoprotein expressing vaccine (VSV-MARV) provided quick protection to animal models against MVD.It is claimed about a candidate vaccine MVA-BN-Filo that contains antigens from both Marburg and Ebola viruses to protect against both the hemorrhagic diseases.Its phase 3 trial against Ebola is ongoing and yet to be tested against MARV.The search is still on for efficient prophylactic and therapeutic (like MARV-specific monoclonal antibody and small-molecule antivirals) interventions against MVD.A monoclonal antibody (MR186-YTE) and antiviral remdesivir combination treated nonhuman primate model against MVD successfully. 46Chimpanzee adenovirus vectored (cAd3-Marburg) vaccine was tried on 40 healthy human volunteers and the clinical response titre was estimated.Although

(
GHS) has worked to improve its monitoring and laboratory service in similar lines, by creating a national action plan for health security (NAPHS).The action plan trains the scientists, doctors, veterinarians, and paramedics through field epidemiology and laboratory training programe (GFELTP) scheme.This programe is in line with the "One Health" concept to educate the diverse healthcare workers through a 360°approach.Developing the state-of-the-art laboratory diagnosis and surveillance capabilities particularly for the lately identified viruses from filovirus, orthomyxovirus, paramyxovirus, and coronavirus families of major health concerns is necessary.The one health workforce (OHW) project is a part of the USAID focusing on intersectoral disease surveillance, training, and outbreak response.

11 |
CONCLUSIONMVD is one of the neglected infectious diseases that can potentially impact public health at the global scale due to its high (∼90%) fatality rate.Recent outbreaks call for broader and detailed studies on this highly virulent zoonotic disease.A glaring reason for the continuous emergence of the MVD-zoonotic spill-over is the chance or deliberate human encounter with the bats in the wild especially near the caves where they primarily dwell.A secondary reason that makes the situation worse is the absence of befitting therapeutic and preventive countermeasures to control MVD disease.Thankfully, large MVD outbreaks are rare although the world has witnessed multiple outbreaks.Also, there is a wide gap on the knowledge of host-virus interactions.Designing evidence-based recommendations to prevent and control MVD is recommended.Implementing "One Health" strategy to know the host-virus interactions need prioritization.Therefore, the necessity of a high-level global cross-discipline joint effort among public health agencies, physicians, paramedics, veterinarians, environmentalists, and policymakers is urgently being felt.
Hemorrhagic fever cases were first detected simultaneously from the Marburg and Frankfurt cities in West Germany, and Belgrade in

were followed up elsewhere. 20 Subsequent outbreaks were in Uganda in 2007, 2012, 2014, and 2017, with 27%-100% case fatality rates. The first MVD case in the Republic of Guinea was reported in August 2021 amid the ongoing COVID-19 pandemic, signaling a new health concern.
although other Chiropterans like H. caffer also are.In view of the fact that MVD is linked to bats, research on bat-colonizing microflora has been of interest.Bats carry Coronavirus, T A B L E 1 Various Marburg virus disease outbreaks reported worldwide.Various vaccines developed against MVD worldwide. 27 Source: Adopted from the CDC (https://www.cdc.gov/vhf/marburg/outbreaks/chronology.html#six).T A B L E 2

Table 2
49,50ls the numerous vaccines developed to counter MVD.Despite the support "One Health" in Ghana, budgeting, coordinating, and executing the cross-sector initiatives were difficult.40Internationalfederationscouldstep up and expedite efforts to support Ghana on this considering the potentially terrible global ramifications of MVD.The spread of MVD must be nipped at the bud before it is too late to avoid the repetition of what was globally encountered with COVID-19 and Ebola.49,50Afterconfirming the presence of Filovirus antibody in Ghanaian fruit-bats, research to comprehend the role of the bats as hosts needs revamping.The world has witnessed 17 reported MARV outbreaks so far in Africa